Recent mouse genetic studies have identified Tbx1 as a major candidate for VCFS/DGS. Ear development in Tbx1 loss of function embryos is severely affected. The inner ear never develops beyond the otic vesicle stage and thus the sensory organs never form. The cochlear vestibular ganglion, which develops from the otocyst rudiment, is also affected in the null mutant mice. In contrast to the lack of sensory organ development, the VIIIth ganglion rudiment is duplicated in the Tbx1 -/- embryos, suggesting that Tbx1 both induces sensory organ formation and suppresses neural fate determination. During mid-gestation, Tbx1 is dynamically expressed in the otic vesicle, in a manner complimentary to the pattern of expression of neural precursor cells. Another domain of Tbx1 expression encompasses the adjacent periotic mesenchyme. I am interested in the distinct roles of Tbx1 in the otic vesicle and in the periotic mesenchyme in the development of the inner ear. For Specific Aim 1, I will determine the role of Tbx1 in neurogenesis versus sensory organ formation, using the conditional inactivating allele. For Specific Aim 2, I will determine the role of Tbx1 in late gestation by inactivating the gene at specific time points beyond the otic vesicle stage.